This proposal is an initial submission from Elizabeth Anne Van Tubergen, DDS for the Ruth L. Kirschstein National Research Service Award (NRSA) for Individual Postdoctoral Fellows (F32). This 2 year award will enable her to complete her graduate education and training in the Oral Health Sciences PhD Program at the University of Michigan School of Dentistry. Additionally, this grant will prepare her to pursue a postdoctoral position upon completion of her PhD and move forward with her detailed career plan to become an independent investigator. The overall objective of this application is to delineate the role of tristetraprolin (TTP), an RNA-binding protein, in head and neck cancer (HNSCC) progression via release of inflammatory cytokines. Understanding how cytokine secretion is regulated will likely identify a treatment target in HNSCC. HNSCC is the sixth most common cancer globally. The 5 year survival rate is poorer than breast cancer or melanoma. There has been no dramatic improvement in survival or development of novel therapeutic agents in >40 years. Tumor-secreted cytokines, such as IL6, TNF1, and COX2, have a crucial role in tumor progression. However, the lack of success in treating HNSCC with anti-tumor agents that target individual cytokines may be due to secretion of multiple cytokines with overlapping functions. What has not been identified is a common regulatory mechanism for multiple cytokines. This knowledge is required in order to develop targeted therapy that ensures success of treatment. The central hypothesis of this proposal is that tumors with downregulated or non- functional TTP exhibit increased secretion of inflammatory cytokines and consequently, behave aggressively. In order to test this hypothesis, we propose to: (1) determine the extent to which downregulation of TTP expression promotes secretion of IL6, TNF1 and COX2, in HNSCC, (2) investigate the extent to which downregulation of TTP expression mediates invasion and tumor progression in HNSCC via upregulation of IL6, TNF1 and COX2. PUBLIC HEALTH RELEVANCE: There have not been any improvements in head and neck cancer treatment in over 40 years. The goal of this application is to identify biomarkers for head and neck cancer in order to elucidate novel therapies to improve cancer treatment. This application will support Dr. Elizabeth Van Tubergen, DDS, PhD candidate for degree, to complete her PhD at the University of Michigan Oral Health Sciences Program.